Immune regulation of complement components is being studied in F1 hybrids from matings of normal (homozygous) males and females homozygous for specific genetic defects in a single complement component. It has been possible to chronically suppress the fifth component of complement in (C5 plus C5 minus) F1 mice but not the fourth component of complement in (C4 plus C4 minus) F1 guinea pigs nor the sixth component of complement in (C6 plus C6 minus) F1 rabbits. However, immune regulation of C4 has been successful in tissue culture systems. To understand the control of normal complement components and their relationship to deficiency states, genetic regulation of complement components is being studied in animal models with known genetic defects in a single component. The inheritance of two structural genes and a deficiency gene for the sixth component of complement has been studied in rabbits. These three genes have been shown to be alleles of the same genetic locus but there is a natural selection against one of the structural genes whose product has unusual functional properties. The major goal of these experiments is to elucidate genetic and immune mechanisms by which biosynthesis of complement components are regulated. In vitro and in vivo experiments are being carried out to identify: 1) the role of antibody and other humoral regulatory factors, 2) the relationship of altered biosynthesis to other cellular functions, and 3) the effect of altered gene products on natural selection. Since complement components are relatively homogenous proteins under simple genetic control, they offer a unique model with which to extend studies of immune regulation into systems consisting of nonlymphoid cell products.